Azacyclic compounds compositions containing them and their use as tachykinin antagonists

ABSTRACT

The present invention relates to compounds of formula (I), and salts and prodrugs thereof, wherein n is 1 , 2 or 3 and where any carbon atom of (CH 2 ) n  may be substituted by R 4  and/or R 5  ; X represents O or S; R 1  represents optionally substituted (CH 2 ) q  phenyl, wherein q is 0, 1, 2 or 3; R 2  represents optionally substituted aryl, heteroaryl, benzhydryl or benzyl; R 4  and R 5  each independently represent H, halo, C 1-6  alkyl, oxo, CO 2  R a  or CONR a  R b  ; R 6  represents H or C 1-6  alkyl; R 7  represents C 1-6  alkyl or optionally substituted phenyl; R 8  represents H, COR a , CO 2  R a , COCONR a  R b , COCO 2  R a , C 1-6  alkyl optionally substituted by a variety of substituents, or C 1-6  alkyl, optionally substituted by oxo, substituted by an optionally substituted aromatic heterocycle. The compounds are tachykinin antagonists useful for treating pain or inflammation, migraine or emesis.

The present application is a National Phase application under 35 U.S.C.§371 of PCT Application No. PCT/EP94/0412, filed Feb. 10, 1994.

This invention relates to a class of azacyclic compounds, which areuseful as tachykinin antagonists. More particularly, the compounds ofthe invention comprise an azacyclic ring system substituted by anarylmethyloxy or arylmethylthio moiety.

The tachykinins are a group of naturally-occurring peptides found widelydistributed throughout mammalian tissues, both within the centralnervous system and in the peripheral nervous and circulatory systems.The three known mammalian tachykinins are as follows:

Substance P therefor

Nedrokinin A therefor

Neurokinin B therefor

For example, substance P is believed inter alia to be involved in theneurotransmission of pain sensations [Otsuka et al, "Role of Substance Pas a Sensory Transmitter in Spinal Cord and Sympathetic Ganglia" in 1982Substance P in the Nervous System, Ciba Foundation Symposium 91, 13-34(published by Pitman) and Otsuka and Yanagisawa, "Does Substance P Actas a Pain Transmitter?" TIPS (Dec. 1987) 8 506-510], specifically in thetransmission of pain in migraine (B. E. B. Sandberg et al, J. Med Chem,(1982) 25 1009) and in arthritis [Levine et al in Science (1984) 226547-549]. These peptides have also been implicated in gastrointestinal(GI) disorders and diseases of the GI tract such as inflammatory boweldisease [Mantyh et. al in Neuroscience (1988) 25 (3) 817-37 and D.Regoli in "Trends in Cluster Headache" Ed. Sicuteri et al ElsevierScientific Publishers, Amsterdam (1987) page 85)] and emesis [F. D.Tattersall et. al., Eur. J. Pharmacel., (1993) 250, R5-R6]. It is alsohypothesised that there is a neurogenic mechanism for arthritis in whichsubstance P may play a role [Kidd et al "A Neurogenic Mechanism forSymmetrical Arthritis" in The Lancet, 11 Nov. 1989 and Gronblad et al"Neuropeptides in Synovium of Patients with Rheumatoid Arthritis andOsteoarthritis" in J. Rheumatol. (1988) 15(12) 1807-10]. Therefore,substance P is believed to be involved in the inflammatory response indiseases such as rheumatoid arthritis and-osteoarthritis [O'Byrne et alin Arthritis and Rheumatism (1990) 33 1023-8]. Other disease areas wheretachykinin. antagonists are believed to be useful are allergicconditions [Hamelet et al Can. J. Pharmacol. Physiol. (1988) 66 1361-7],immunoregulation [Lotz et al Science (1988) 241 1218-21 and Kimball etal, J. Immunol. (1988) 141 (10) 3564-9] vasodilation, bronchospasm,reflex or neuronal control of the viscera [Mantyh et al, PNAS (1988) B53235-9]and, possibly by arresting or slowing β-amyloid-mediatedneurodegenerative changes [Yankner et E1 Science, (1990) 250, 279-82] insenile dementia of the Alzheimer type, Alzheimer's disease and Down'sSyndrome.

Tachykinin antagonists may also be useful in the treatment of small cellcarcinomas, in particular small cell lung cancer (SCLC) [Langdon et.al., Cancer Research (1992) 52, 4554-7].

Substance P may also play a role in demyelinating diseases such asmultiple sclerosis and amyotrophic lateral sclerosis [J. Luber-Narod et.al., poster presented at C.I.N.P. XVIIIth Congress, 28th Jun.-2nd Jul.,1992], and in disorders of bladder function such as bladder detrusorhyper-reflexia (Lancet, 16th May, 1992, 1239).

It has furthermore been suggested that tachykinins have utility in thefollowing disorders: depression, dysthymic disorders, chronicobstructive airways disease, hypersensitivity disorders such as poisonivy, vasospastic diseases such as angina and Reynauld's disease,fibrosing and collagen diseases such as scleroderma and eosinophillicfascioliasis, reflex sympathetic dystrophy such as shoulder/handsyndrome, addiction disorders such as alcoholism, stress related somaticdisorders, neuropathy, neuralgia, disorders related to immuneenhancement or suppression such as systemic lupus erythmatosis (Europeanpatent specification no. 0 436 334), ophthalmic disease such asconjuctivitis, vernal conjunctivitis.. and the like, and cutaneousdiseases such as contact dermatitis, atropic dermatitis, urticaria, andother eczematoid dermatitis (European patent specification no. 0 394989).

In view of their metabolic instability, peptide derivatives are likelyto be of limited utility as therapeutic.agents. It is for this reasonthat non-peptide tachykinin antagonists are sought.

In essence, this invention provides a class of potent non-peptidetachykinin antagonists. By virtue of their non-peptide nature, thecompounds of the present invention do not suffer from the shortcomings,in terms of metabolic instability, of the known peptide-based tachykininantagonists discussed above.

The present invention provides a compound of formula (I), or a salt orprodrug thereof: ##STR2## wherein n is 1, 2 or 3 and where any carbonatom of (CH₂)_(n) may be substituted by R⁴ and/or R⁵ ;

X represents O or S;

R¹ represents (CH₂)_(q) phenyl, wherein q is 0, 1, 2 or 3, which may beoptionally substituted in the phenyl ring by 1, 2 or 3 groups selectedfrom C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynl, halo, cyano, nitro,triluoromethyl, trimethylsilyl, --OR^(a), SR^(a), SOR^(a), SO₂ R^(a),--NR^(a) R^(b), --NR^(a) COR^(b), --NR^(a) CO₂ R^(b), --CO₂ R^(a) andCOLNR^(a) R^(b) ;

R² represents aryl selected from phenyl and naphthyl; heteroarylselected from indazolyl, thienyl, furyl, pyridyl, thiazolyl, tetrazolyland quinolyl; benzhydryl; or benzyl; wherein each aryl or heteroarylmoiety may be substituted by C₁₋₆ alkyl, C₁₋₆ alkoxy, halo ortrifluoromethyl;

R⁴ and R⁵ each independently represent H, halo, C₁₋₆ alkyl, oxo, CO₂R^(a) or CONR^(a) R^(b) ;

R⁶ represents H or C₁₋₆ alkyl;

R⁷ represents C₁₋₆ alkyl or phenyl optionally substituted by 1, 2 or 3groups selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, halo,cyano, nitro, trifluoromethyl, trimethylsilyl, --OR^(a), SR^(a),SOR^(a), SO₂ R^(a), --NR^(a) R^(b), --NR^(a) COR^(b), --NR^(a) CO₂R^(b), --CO₂ R^(a) and --CONR^(a) R^(b) ;

R⁸ represents H, COR^(a), CO₂ R^(a) COCONR^(a) R^(b), COCO₂ R^(a), C₁₋₆alkyl optionally substituted by a group selected from (CO₂ R^(a),CONR^(a) R^(b), hydroxy, cyano, COR^(a), NR^(a) R^(b), C(NOH)NR^(a)R^(b), CONHphenyl(C₁₋₄ alkyl) COCO₂ R^(a), CONHNR^(a) R^(b), C(S) NR^(a)R^(b), CONR^(a) C₁₋₆ alkylR¹² , CONR¹³ C₂₋₆ alkynyl, CONR¹³ C₂₋₆alkenyl, COCONR^(a) R^(b), CONR^(a) C(NR^(b))NR^(a) R^(b), CONR^(a)heteroaryl, and phenyl optionally substituted by one or moresubstituents selected from C₁₋₆ alkyl, C₁₋₆ alkoxy, halo andtrifluoromethyl) or C₁₋₆ alkyl, optionally substituted by Oxo,substituted by an optionally substituted aromatic heterocycle;

R^(a) and R^(b) each independently represent H, C₁₋₆ alkyl,trifluoromethyl or phenyl optionally substituted by C₁₋₆ alkyl, halo ortrifluoromethyl;

R¹² represents OR^(a), CONR^(a) R^(b) or heteroaryl; and

R¹³ represents H or C₁₋₆ alkyl.

As used herein, the definition of each expression, when it occurs morethan once in any structure, is intended to be independent of itsdefinition elsewhere in the same structure.

The alkyl, alkenyl and alkynyl groups referred to with respect to theabove formula may represent straight, branched or cyclic groups. Thus,for example, suitable alkyl groups include methyl, ethyl, n- oriso-propyl, n-, sec-, iso- or tert-butyl, cyclopropyl, cyclobutyl,cyclopentyl or cyclohexyl, and cycloalkyl-alkyl groups such ascyclopropylmethyl; suitable alkenyl groups include vinyl and allyl; andsuitable alkynyl groups include propargyl.

The term "halo" as used herein includes fluoro, chloro, bromo and iodo,especially chloro and fluoro.

The present invention includes within its scope prodrugs of thecompounds of formula (I) above. In, general, such prodrugs will befunctional derivatives of the compounds of formula (I) which are readilyconvertible in vivo into the required compound of formula (I).Conventional procedures for the selection and preparation of suitableprodrug derivatives are described, for example, in "Design of Prodrugs"ed H. Bundgaard, Elsevier, 1985.

The compounds according to the invention may exist both as enantiomersand as diastereomers. In particular, the relative orientation of the 2-and 3-substituents on the azacyclic ring may give rise to cis and transdiastereoisomers, of which the cis stereochemistry is preferred. It isto be understood that all such isomers and mixtures thereof areencompassed within the scope of the present invention.

Preferably n is 2 or 3, more preferably 3.

Preferably X represents O.

Preferably q is O and R¹ represents substituted phehyl. When R¹ issubstituted phenyl suitable substituents include nitro, trifluoromethyl,trimethylsily, bromo, chloro, fluoro, iodo, cyano, methyl, ethyl,cyclopropyl, vinyl, methoxy, phenoxy, amino and carbonylmethoxy.Preferably R¹ represents phenyl substituted by one or more groupsselected from methyl, trifluoromethyl, chloro and t-butyl.

Preferably R¹ represents disubstituted phenyl, more preferably3,5-disubstituted phenyl such as 3,5-dichlorophenyl or3,5-bis(trifluoromethyl)phenyl, or monosubstituted phenyl, such as3-substituted phenyl, e.g. 3-t-butylphenyl.

Preferably R² represents unsubstituted benzhydryl, phenyl substituted byhalo such as chloro, for example 4-chlorophenyl, or unsubstitutedphenyl, more preferably unsubstituted phenyl.

Preferably R⁴ and R⁵ both represent H.

Suitable values for R⁶ include H, methyl and ethyl. Preferably R⁶represents H or methyl, more preferably H.

Preferably R⁷ represents C₁₋₆ alkyl, such as methyl or ethyl, morepreferably methyl.

When R⁸ represents C₁₋₆ alkyl, optionally substituted by oxo,substituted by a substituted aromatic heterocycle, suitable substituentsin the heterocyclic ring include C₁₋₆ alkyl, C₁₋₆ alkoxy, oxo, thioxo,halo, trifluoromethyl, NR^(a) R^(b), NR^(a) COR^(b), CONR^(a) R^(b), CO₂R^(a), SO₂ R^(a) and CH₂ OR^(a), where R^(a) and R^(b) are as previouslydefined.

Preferably R⁸ represents C₁₋₃ alkyl such as methyl, ethyl or i-propylsubstituted by a substituted or unsubstituted aromatic heterocycle.Suitable heterocycles include thienyl, furyl, pyrrolyl, pyridyl,pyrazolyl, triazolyl, tetrazolyl, thiazolyl, pyrazinyl, pyridazinyl,oxazolyl, oxadiazolyl, thiadiazolyl, isoxazolyl, quinolyl, isothiazolyl,imidazolyl, benzimidazolyl, benzoxazolyl, benzothiophenyl, benzofuranyland indolyl.

In one group of compounds according to the invention R⁸ represents CH₂-Het, CH(CH₃)-Het, C(CH₃)₂ -Het or C(O)-Het, where Het is pyrrolyl,pyrazolyl, pyrazinyl, pyridazinyl, oxadiazolyl, thiadiazolyl,imidazolyl, benzimidazolyl, benzoxazolyl, benzothiophenyl, benzofuranylor indolyl.

Preferably R⁸ represents CH₂ -Het,CH(CH₃)-Het, C(CH₃)₂ -Het or C(O)-Hetwhere Het is substituted or unsubstituted oxazolyl, oxadiazolyl,tetrazolyl, thiazolyl, thiadiazolyl, furanyl, thienyl, triazolyl,pyrazinyl, pyridyl, pyridazinyl, imidazolyl or benzimidazolyl. Morepreferably Het is triazolyl or triazolyl substituted by oxo.

Other suitable values for R⁸ include H, COR^(a), CO₂ R^(a), COCONR^(a)R², COCO₂ R^(a), C₁₋₆ alkyl and C₁₋₆ alkyl substituted by a groupselected from CO₂ R^(a), CONR^(a) R^(b), CN, C(NOH)NR^(a) R^(b),CONHphenyl(C₁₋₄ alkyl), optionally substituted phenyl, CONHNR^(a) R^(b),COCONR^(a) R^(b), CONR^(a) C(NH)NH₂, CSNR^(a) R^(b), CONR¹³ C₂₋₆alkynyl, CONR^(a) C₁₋₆ alkylR¹² and CONR^(a) heteroaryl.

It will be appreciated that, when R⁸ comprises a heteroaryl moietysubstituted by an oxo or thioxo substituent, different tautomeric formsare possible so that the substituent on the heteroaryl moiety may berepresented as ═O or --OH, or ═S or --SH, respectively. For theavoidance of doubt, all such tautomeric forms are embraced by thepresent invention.

A particular sub-class of compounds according to the invention isrepresented by compounds of formula (Ia), and salts and prodrugsthereof: ##STR3## wherein R², R⁴, R⁵, R⁶, R⁸, X and n are as defined forformula (I) above;

R¹⁵ represents C₁₋₆ alkyl; and

R¹⁶ represents phenyl optionally substituted by 1, 2 or 3 groupsselected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, halo, cyano,nitro, trifluoromethyl, trimethylsilyl, --OR^(a), SR^(a), SOR^(a), SO₂R^(a), --NR^(a) R^(b), --NR^(a) COR^(b), --NR^(a) CO₂ R^(b), --CO₂ R^(a)and --CONR^(a) R^(b).

A further sub-class of compounds according to the invention isrepresented by compounds of formula (Ib) and salts and prodrugs thereof:##STR4## wherein X represents 0 or S, preferably O;

R⁸ is as defined for formula (I);

R¹⁷ represents phenyl or benzhydryl wherein any of the phenyl rings ofthe phenyl or benzhydryl moieties may optionally be substituted by haloor trifluoromethyl, preferably unsubstituted phenyl;

R¹⁸ is methyl;

R¹⁹ is H or methyl; and

R²⁰ and R²¹ independently represent H C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, chloro, bromo, fluoro, iodo, cyano, nitro, trifluoromethyl,trimethylsilyl OR^(a), SR^(a) SOR^(a), SO₂ R^(a), NR^(a) R^(b), NR^(a)COR^(b), NR^(a) CO₂ R^(b), CO₂ R^(a) or CONR^(a) R^(b), where R^(a) andR^(b) are as previously defined.

Particular values of R²⁰ and R²¹ include methyl, ethyl, t-butyl, chloroand trifluoromethyl. Preferably R²⁰ and R²¹ are both other than hydrogenand are located at the 3- and 5-positions of the phenyl ring.

A preferred group of compounds according to the invention are compoundsof formula (Ib) wherein R⁸ is optionally substituted triazolyl.

Specific compounds within the scope of the present invention include:(2s,3S)3-(1-(3,5-bis(trifluoromethyl)phenyl)ethyloxy)-2-phenylpiperdine;and salts and prodrugs thereof.

For use in medicine, the salts of the compounds of formula (I) will bepharmaceutically acceptable salts. Other salts (such as thedibenzoyltartrate salts) may, however, be useful in the preparation ofthe compounds according to the invention or of their pharmaceuticallyacceptable salts. Suitable pharmaceutically acceptable salts of thecompounds of this invention include acid addition salts which may, forexample, be formed by mixing a solution of the compound according to theinvention with a solution of a pharmaceutically acceptable acid such ashydrochloric acid, sulphuric acid, oxalic acid, fumaric acid, maleicacid, succinic acid, acetic acid, citric acid, tartaric acid, carbonicacid, phosphoric acid or p-toluenesulphonic acid. Salts of amine groupsmay also comprise quaternary ammonium salts in which the amino nitrogenatom carries a suitable organic group such as an alkyl, alkenyl, alkynylor aralkyl moiety. Furthermore, where the compounds of the inventioncarry an acidic moiety, suitable pharmaceutically acceptable saltsthereof may include metal salts such as alkali metal salts, e.g. sodiumor potassium salts; and alkaline earth metal salts, e.g. calcium ormagnesium salts.

Preferred salts of the compounds according to the invention include thehydrochloride and p-toluenesulphonic acid salts.

The invention also provides pharmaceutical compositions comprising acompound of this invention in association with a pharmaceuticallyacceptable carrier. Preferably these compositions are in unit dosageforms such as tablets, pills, capsules, powders, granules, solutions orsuspensions, or suppositories, for oral, parenteral or rectaladministration, or administration by inhalation or insufflation.

For preparing solid compositions such as tablets, the principal activeingredient is mixed with a pharmaceutical carrier, e.g. conventionaltableting ingredients such as corn starch, lactose, sucrose, sorbitol,talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, andother pharmaceutical diluents, e.g. water, to form a solidpreformulation composition containing a homogeneous mixture of acompound of the present invention, or a non-toxic pharmaceuticallyacceptable salt thereof. When referring to these preformulationcompositions as homogeneous, it is meant that the active ingredient isdispersed evenly throughout the composition so that the composition maybe readily subdivided into equally effective unit dosage forms such astablets, pills and capsules. This solid preformulation composition isthen subdivided into unit dosage forms of the type described abovecontaining from 0.1 to about 500 mg of the active ingredient of thepresent invention. The tablets or pills of the novel composition can becoated or otherwise compounded to provide a dosage form affording theadvantage of prolonged action. For example, the tablet or pill cancomprise an inner dosage and an outer dosage component, the latter beingin the form of an envelope over the former. The two components can beseparated by an enteric layer which serves to resist disintegration inthe stomach and permits the inner component to pass intact into theduodenum or to be delayed in release. A variety of materials can be usedfor such enteric layers or coatings, such materials including a numberof polymeric acids and mixtures of polymeric acids with such materialsas shellac, cetyl alcohol and cellulose acetate.

The liquid forms in which the novel compositions of the presentinvention may be incorporated for administration orally or by injectioninclude aqueous solutions, suitably flavoured syrups, aqueous or oilsuspensions, and flavoured emulsions with edible oils such as cottonseedoil, sesame oil, coconut oil or peanut oil, as well as elixirs andsimilar pharmaceutical vehicles. Suitable dispersing or suspendingagents for aqueous suspensions include synthetic and natural gums suchas tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose,methylcellulose, polyvinyl-pyrrolidone or gelatin.

Compositions for inhalation or insufflation include solutions andsuspensions in pharmaceutically acceptable, aqueous or organic solvents,or mixtures thereof, and powders. The liquid or solid compositions maycontain suitable pharmaceutically acceptable; excipients as set outabove. Preferably the compositions are adminsitered by the oral or nasalrespiratory route for local or systemic effect. Compositions inpreferably sterile pharmaceutically acceptable solvents may be nebulisedby use of inert gases. Nebulised solutions may be breathed directly fromthe nebulising device or the nebulising device may be attached to a facemask, tent or intermittent positive pressure breathing machine.Solution, suspension or powder compositions may be administered,preferably orally or nasally, from devices which deliver the formulationin an appropriate manner.

The compounds of formula (I) are of value in the treatment of a widevariety of clinical conditions which are characterised by the presenceof an excess of tachykinin, in particular substance P, activity. Thesemay include disorders of the central nervous system such as anxiety,depression, psychosis and schizophrenia; epilepsy; neurodegenerativedisorders such as dementia, including senile dementia of the Alzheimertype, Alzheimer's disease and Down's syndrome; demyelinating diseasessuch as MS and ALS and other neuropathological disorders such asperipheral neuropathy, for example, diabetic or chemotherapy-indncedneuropathy, and postherpetic and other neuralgias; small cell carcinomassuch as small cell lung cancer (SCLC); respiratory diseases particularlythose associated with excess mucus sedretion such as chronic obstructiveairways disease, bronchopneumonia, chronic bronchitis, cystic fibrosis,bronchospasm and asthma; inflammatory diseases such as inflammatorybowel disease, psoriasis, fibrositis, osteoarthritis and rheumatoidarthritis; allergies such as eczema and rhinitis; hypersensitivitydisorders such as poison ivy; ophthalmic diseases such asconjunctivitis, vernal conjunctivitis, and the like; cutaneous diseasessuch as contact dermatitis, atropic dermatitis, urticaria, and othereczematoid dermatitis; addiction disorders such as alcoholism; stressrelated somatic disorders; reflex sympathetic dystrophy such asshoulder/hand syndrome; dysthymic disorders; adverse immunologicalreactions such as rejection of transplanted tissues and disordersrelated to immune enhancement or suppression such as systemic lupuserythematosis; gastrointestinal (GI) disorders and diseases of the GItract such as disorders associated with the neuronal control of viscerasuch as ulcerative colitis, Crohn's disease and incontinence; emesis,including acute, delayed and anticipatory emesis, for example, inducedby chemotherapy, radiation, toxins, pregnancy, vestibular disorders,surgery, migraine and variations in intercranial pressure; disorders ofbladder function such as bladder detrusor hyper-reflexia; fibrosing andcollagen diseases such as scleroderma and eosinophilic fascioliasis;disorders of blood flow caused by vasodilation and vasospastic diseasessuch as angina, migraine and Reynaud's disease; and pain or nociception,for example, that attributable to or associated with any of theforegoing conditions, especially the transmission of pain in migraine.

The compounds of formula (I) are also of value in the treatment of acombination of the above conditions, in particular in the treatment ofcombined post-operative pain and post-operative nausea and vomiting.

The compounds of formula (I) are particularly useful in the treatment ofpain or nociception and/or inflammation and disorders associatedtherewith such as, for example, neuropathy, such as diabetic andchemotherapy-induced neuropathy, postherpetic and other neuralgias,asthma, osteroarthritis, rheumatoid arthritis and especially migraine.

The present invention further provides a compound of formula (I) or saltor prodrug thereof for use in therapy.

According to a further or alternative aspect, the present inventionprovides a compound of formula (I) or a salt or prodrug thereof for usein the manufacture of a medicament for the treatment of physiologicaldisorders associated with an excess of tachykinins, especially substanceP.

The present invention also provides a method for the treatment orprevention of physiological disorders associated with an excess oftachykinins, especially substance P, which method comprisesadministration to a patient in need thereof of a tachykinin reducingamount of a compound of formula (I), or a salt or prodrug thereof, or acomposition comprising a compound of formula (I), or a salt or prodrugthereof.

In the treatment of the conditions associated with an excess oftachykinins, a suitable dosage level is about 0.001 to 50 mg/kg per day,in particular about 0.01 to about 25 mg/kg, such aS from about 0.05 toabout 10 mg/kg per day. For example, in the treatment of conditionsinvolving the neurotransmission of pain sensations, a suitable dosagelevel is about 0.001 to 25 mg/kg per day, preferably about 0.005 to 10mg/kg per day, and especially about 0.005 to 5 mg/kg per day. Thecompounds may be administered on a regimen of 1 to 4 times per day,preferably once or twice per day.

The compounds according to the invention may be prepared by a processwhich comprises reacting a compound of formula (II) with a compound offormula (III): ##STR5## wherein R¹, R², R⁴, R⁵, R⁶, R⁷ and n are asdefined for formula (I), R⁸ is as defined for formula (I) except that,when R⁸ is H it is replaced by a suitable protecting group, such as CO₂(C₁₋₆ alkyl); and one of R³⁰ and R³¹ represents a leaving group and theother of R³⁰ and R³¹ represents XH, where X is as defined for formula(I); in the presence of a base, followed by deprotection, if required.

Suitably R³⁰ represents XH and R³¹ represents a leaving group.

Suitable leaving groups include halo, e.g. chloro, bromo or iodo, orsulphonate derivatives such as tosylate, mesylate or triflate.

The reaction is conveniently carried out in a suitable organic solvent,such as an ether, e.g. 1,2-dimethoxyethane, at a temperature in theregion of 0° C. Favoured bases of use in the reaction include alkalimetal amides and hydrides, such as potassium bis(trimethylsilyl)amide orpotassium hydride. Suitably, potassium bis(trimethylsilyl)amide is used.

Alternatively, compounds of formula (I) may be prepared from differentcompounds of formula (I) by interconversion processes. In particular,interconversion processes may be used to vary the group R⁸. For example,compounds of formula (I) wherein R⁸ is other than H may be prepared fromthe corresponding compounds of formula (I) wherein R⁸ is H by reactionwith a reagent suitable to introduce the group R⁸, for example, a halideor acyl halide, or corresponding mesylate or tosylate, of formula R⁸ -L,where L represents halo, such as chloro, bromo or iodo, methylsulphonateor p-toluenesulphonate,or any other suitable leaving group, in thepresence of a base. Suitable bases of use in the reaction includeinorganic bases such as alkali metal carbonates, for example, potassiumcarbonate. Conveniently the reaction is effected in a suitable organicsolvent, for example, dimethylformamide.

Compounds of formula (I) wherein R⁸ is COR⁹ may be prepared fromcompounds of formula (I) wherein R⁸ is H by, for example, reaction withan appropriate acid anhydride.

Compounds of formula (I) wherein R⁸ is C₁₋₆ alkyl may be prepared fromcorresponding compounds of formula (I) wherein R⁸ is COR⁹ by reductionusing, for example, borane or a borohydride such as sodiumcyanoborohydride.

Compounds of formula (I) wherein R⁸ is C₁₋₆ alkyl substituted byCONR^(a) R^(b) may be prepared from corresponding compounds of formula(I) wherein R⁸ is C₁₋₆ alkyl substituted by CO₂ R^(a) by treatment withammonia or an amine of formula NR^(a) R^(b).

Compounds of formula (I) wherein R⁸ is C₁₋₆ alkyl substituted by5-oxadiazolyl may be prepared from compounds of formula (I) wherein R⁸is C₁₋₆ alkyl substituted by CH₂ R^(a), where R^(a) represents C₁₋₆alkyl, by reaction with a compound of formula (IV) ##STR6## wherein R³²represents H or a suitable substituent, in the presence of a base.

Suitable bases of use in the reaction include alkali metals, such as,for example, sodium, and alkali metal hydrides, such as, for example,sodium hydride.

The reaction is conveniently effected in a suitable organic solvent.Which solvents will be appropriate will depend on the nature of the baseused. For example, where the base used is an alkali metal, suitablesolvents will include alcohols, for example, ethanol, whereas where thebase used is an alkali hydride, suitable solvents will include ethers,for example, tetrahydrofuran.

Preferably the reaction is conducted at elevated temperature, such asthe reflux temperature of the chosen solvent.

Compounds of formula (I) wherein R⁸ is C₁₋₆ alkyl substituted bytetrazolyl may be prepared from compounds of formula (I) wherein R⁸ isC₁₋₆ alkyl substituted by cyano by treatment with an alkali metal axide,such as sodium azide.

Compounds of formula (I) wherein R⁸ is C₁₋₆ alkyl substituted bythiazolyl may be prepared from compounds of formula (I) wherein R⁸ isC₁₋₆ alkyl substituted by CSNH₂ by reaction with a compound of formulaHal--CH₂ C(O)--R⁶⁰, where Hal is halo such as bromo, chloro or iodo, andR⁶⁰ represents H or a suitable substituent.

Compounds of formula (I) wherein R⁸ is C₁₋₆ alkyl substituted bythioxotriazolyl may be prepared from compounds of formula (I) wherein R⁸is C₁₋₆ alkyl substituted by CONHNH₂ by reaction with a compound offormula R⁶¹ NCS, wherein R⁶¹ represents H or a suitable substituent suchas C₁₋₆ alkyl, in the presence of a base.

Suitable bases of use in the reaction include organic bases such as, forexample, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU). The reaction isconveniently effected in a suitable orgainc solvent, such as alcohol,e.g. butanol.

Compounds of formula (I) wherein R⁸ is C₁₋₆ alkyl substituted byunsubstituted or substituted. triazolyl may be prepared from a compoundof formula (I) wherein R⁸ is H, by reaction with a compound of formula(V) ##STR7## wherein Hal is as previously defined, m is 1, 2, 3, 4, 5 or6 and R⁶² is H or a group suitable as a substituent of the triazolering, or convertable to such a group under the reaction conditions, inthe presence of a base.

Suitable bases of use in the reaction include alkali metal carbonates,such as, for example, potassium carbonate.

Suitably R⁶² represents H, OCH₃ (which is converted to an oxosubstituent under the reaction conditions) or CONH₂.

The reaction is conveniently effected in an anhydrous organic solvent,such as, for example, anhydrous dimethylformamide, preferably atelevated temperature, such as about 60° C.

Compounds of formula (I) wherein R⁸ represents C₁₋₆ alkyl substituted byCONR^(a) C₁₋₆ alkylR¹² or CONR^(a) heteroaryl may be prepared fromcompounds of formula (I) wherein R⁸ is C₁₋₆ alkyl substituted by CO₂ Hby reaction with an amine of formula HNR^(a) C₁₋₆ alkylR¹² or HNR^(a)heteroaryl.

The intermediates of formula (II) above wherein R³⁰ is SH may beprepared from the corresponding intermediates of formula (II) whereinR³⁰ represents OH by treating the latter compound with Lawesson'sreagent or phosphorus pentasulphide in a suitable solvent, e.g.pyridine, at ambient or elevated temperatures, suitably at refluxtemperature.

Intermediates of formula (II) above wherein R³⁰ is OH may be preparedfrom corresponding compounds of formula (VI): ##STR8## wherein R², R⁴,R⁵ and R⁸ are as defined for formula (II) above, x is 1 or 2 and R⁵⁰ isan optional carbonyl group, by reduction. Suitable reducing agents willbe readily apparent to one skilled in the art and include, for example,metallic hydrides, such as lithium aluminium hydride or, preferably,sodium borohydride.

Intermediates of formula (II) wherein R³⁰ is a leaving group may beprepared from compounds of formula (II) wherein R³⁰ is OH, for example,by reaction with a thionyl halide, a mesyl halide or a tosyl halide.

Where they are not commercially available, the intermediates of formula(III) above may be prepared by the procedures described in theaccompanying Examples or by alternative procedures which will be readilyapparent to one skilled in the art.

Compounds of formula (VI) wherein x is 1, the carbonyl group R⁵⁰ isabsent, and R⁵ represents CO₂ (C₁₋₆ alkyl), may be prepared by reactionof compounds of formula (VII) with compounds of formula (VIII): ##STR9##wherein R² is as above defined, R^(d) represents C₁₋₆ alkyl and CO₂R^(e) is R⁵ ; in in the presence of a base.

Suitable bases include alkali metal hydrides, such as sodium hydride,and alkali metal alkoxides, such as sodium butoxide. The reaction isconveniently effected in a suitable organic solvent, such as ahydrocarbon, for example, benzene or toluene, or an ether, for exampletetrahydrofuran.

Compounds of formula (VI) wherein R⁵⁰ is absent and R⁵ represents CO₂(C₁₋₆ alkyl) (VIB), may be prepared by reaction of a compound of formula(VII) with a compound of formula (VIIIA) ##STR10## wherein x is 1 or 2and Hal represents halo, such as chloro, bromo or iodo, and CO₂ ^(Re) isas above defined, in the presence of a base, as above described.

Further procedures for the preparation of compounds of formula (VI)using the Dieckmann reaction will be apparent to those skilled in theart and are described in the accompanying examples.

Compounds of formula (VI) wherein R⁵ is other than CO₂ (C₁₋₆ alkyl) maybe prepared from compounds of formula (VI) wherein R⁵ represents CO₂(C₁₋₆ alkyl) by decarboxylation using, for example, oxalic acid.

Alternatively, compounds of formula (VI) wherein x is 2 may be preparedfrom enamines of formula (IX): ##STR11## according to the method ofCervinka et al, Collect. Czech. Chem. Commun., 1988, 53, 308-10.

Compounds of formula (VI) wherein x is 2 and the carbonyl group R⁵⁰ ispresent may be prepared from intermediates of formula (X): ##STR12## byozonolysis, or by means of the Nef reaction. Suitable reagents andconditions are described in Organic Reactions, 38, 655.

Compounds of formula (VI) wherein one or both of R⁴ and R⁵ representshalo, C₁₋₆ alkyl, CONR^(10R11) or CO₂ R¹⁰ may be prepared fromappropriately substituted analogues of the compounds of formulae (VII),(VIII) and (VIIIA), or by appropriate interconversion procedures whichwill be readily apparent to those skilled in the art.

Intermediates of formula (VII) wherein R^(d) is C₁₋₆ alkyl (VIIA) may beprepared from the corresponding compounds of formula (VII) wherein R^(d)is H (VIIB), by conventional methods.

Intermediates of formula (VIIB) may be prepared from the compound offormula (XI): ##STR13## by reaction witff a compound R² -Hal, wherein R²is as above defined and Hal is halo, such as bromo, chloro or iodo, inthe presence of a base, followed by hydrolysis and suitable modificationof the nitrogen substituent using conventional methods.

Suitable bases of use in the reaction include metal hydroxides, forexample, sodium hydroxide. The reaction is conveniently effected in amixture of water and a suitable organic solvent, such as a hydrocarbon,for example, toluene, in the presence of a phase transfer catalyst, suchas benzyltrimethylammonium chloride.

Hydrolysis is conveniently effected by heating a solution of the productof reaction between the compound of formula (X) and R² -Hal inconcentrated hydrochloric acid, at reflux.

The compound of formula (XI) is commercially available.

Intermediates of formula (X) are prepared as described in EuropeanPatent Application No. 0 436 334.

Compounds of formula R² -Hal may be prepared according to the proceduredescribed by E. J. Corey, Tetrahedron Lett., 1972, 4339.

Where the above-described process for the preparation of the compoundsaccording to the invention gives rise to mixtures of stereoisomers theseisomers may, if desired, be separated, suitably by conventionaltechniques such as preparative chromatography.

The novel compounds may be prepared in racemic form, or individualenantiomers may be prepared either by enantiospecific synthesis or byresolution. For example, intermediate alcohols of formula (II), whereinR³⁰ is OH, may be resolved into their component enantiomers by standardtechniques, such as the formation of diastereomeric esters or amides,followed by chromatographic separation or separation by fractionalcrystallization and removal of the chiral auxiliary. The diastereomericalcohols can then be used to prepare optically pure compounds of formula(I).

During any of the above synthetic sequences it may be necessary and/ordesirable to protect sensitive or reactive groups on any of themolecules concerned. This may be achieved by means of conventionalprotecting groups, such as those described in Protective Groups inOrganic Chemistry, ed. J. F. W. McOmie, Plenum Press, 1973; and T. W.Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, JohnWiley & Sons, 1991. The protecting groups may be removed at a convenientsubsequent stage using methods known from the art.

The exemplified compounds of this invention were tested by the methodsset out at pages 36 to 39 of International patent specification No. WO93/01165. The compounds were found to be active with IC₅₀ nM at the NK1receptor of less than 150 nM.

The compounds of this invention may be formulated as specificallyillustrated at pages 35 to 36 of International patent specification No.WO 93/01165.

The following Examples illustrate the preparation of compounds accordingto the invention.

EXAMPLE 1 (2S,3S) 3-(1-(3,5-Bis(trifiuoromethyl)phenyl)ethyl)oxy)-2-phenylpiperidine hydrochloride salt

a) trans-3-Nitro-6-oxo-2-phenylpiperidine

Methyl 4-nitrobutyrate (1) (240 g, 1.63 mol), benzaldehyde (189 g, 1.78mol), ammonium acetate (164 g, 2.12 mol) and ethanol (1680 ml) wereplaced in a 3-liter 3-necked flask equipped with a mechanical stirrer,under an atmosphere of nitrogen. The mixture was heated under reflux forfour hours to yield an orange solution which crystallised on cooling.The crystalline product was isolated by filtration, washed with ethanol,ether and then dried under vacuum to affordtrans-3nitro-6-oxo-2-phenylpiperidine 304 g (85%): m.p. 174°-175° C.; ¹H NMR (360 MHz, CDCl₃) δ2.28-2.38 (1H, m; CHH), 2.51-2.71 (3H, m, CH₂+CHH), 4.69-4.74 (1H, m, CHNO₂), 5.25 (1H, d, J=6.0 Hz, PhCHN), 6.0 (1H,brs, NH), 7.31-7.35 (2H, m, ArH), 7.38-7.45 (3H, m, ArH); ¹³ C NMR(CDCl₃ /DMSO), 22.92 (CH₂), 27.62 (CH₂), 58.58 (PhCHN), 85.01 (CNO₂),126.47 (Ar), 129.02 (Ar), 129.17 (Ar), 137.85 (Ar), 169.55 (C═O);Calculated for C₁₁ H₁₂ N₂ O₃ ; C, 59.99; H, 5.49; N, 12.72. Found: C,60.07; H, 5.60; N, 12.76%.

b) 2.5-Dioxo-6-phenylpiperidine

Method 1

trans-3 -Nitro-6-oxo-2-phenylpiperidine (80 g, 0.364 mol) was suspendedin methanol:dichloromethane (Example 1a, 1:1, 500 ml) under nitrogen.The suspension was cooled to 0° C. and potassium t-butoxide (44.8 g, 0.4mol) was added in portions over 30 mins. The cooling bath was thenremoved and the solution stirred for a further 15 mins to afford a clearyellow solution. The solution was then cooled to -78° C. and ozonebubbled through the reaction mixture for 4.5 hrs, the flow of ozone wasthen stopped and the mixture purged with a stream of nitrogen. Anhydrousdimethyl sulphide (53 ml, 0.73 mol) was then added dropwise and thereaction mixture allowed to warm to room temperature. The solvent wasthen removed at reduced pressure and the residual orange solid dissolvedin dichloromethane (800 ml), washed with water (2×200 ml), dried(MgSO₄), the solvent was then removed at reduced pressure. The residuewas suspended in ether, filtered, and the pale yellow crystalline solidwashed with ether (3×100ml) and dried under vacuum to afford2,5-dioxo-6-phenylpiperidine (54 g, 78%): m.p. 160°-164° C.; ¹ H NMR(360 MHz, DMSO-d₆) δ2.55-2.58 (2H, m, CH₂), 2.63-2.70 (2H, m, CH₂),2.5-2.9 (4H, m, CH₂ CH₂), 4.96 (1H, d, J=2.4 Hz, PhCH), 7.4-7.7 (5H, m,Ar), 8.2 (1H, brs, NH); m/z (CI⁺) 207 (M+NH₄ +), 190 (M+H); Calculatedfor C₁₁ H₁₁ NO₂ C; 69.83; H, 5.86; N, 7.40%. Found C, 70.04; H, 5.77; N,7.60%.

Method 2

To a 5L flask containing ammonium acetate (450g) which had beenthoroughly purged with nitrogen was added a freshly prepared solution oftitanium trichloride (300 g, 1.95 mol) in deoxygenated water (2.1L) withice-bath cooling. To the resulting green solution was added a solutionof trans-3-nitro-6-oxo-2-phenylpiperidine (Example 1a, 90 g, 0.409 mol)and sodium methoxide (27 g, 0.5 mol) in methanol (750 ml). The solutionwas stirred for 1 hr at 0° C. and for a further 1 hr at roomtemperature. Concentrated hydrochloric acid (240 ml) was added dropwise,and the resulting mixture extracted with ethyl acetate (1000 ml, 3×500ml). The combined organic extracts were washed with saturated brine(1000 ml), dried (MgSO₄), and evaporated under reduced pressure. Theresidue was suspended in ether and filtered and the pale yellowcrystalline solid was washed with ether (3×100 ml) and dried in vacuo toafford 2,5-dioxo-6-phenylpiperidine (58 g, 75%): m.p. 160°-164° C.

c) (±)-cis-3-Hydroxy-2-phenylpiperidine 4-toluenesulphonate salt

Sodium borohydride (3.8 g, 0.1 mol) was added portionwise to a cooled(-10° C.) stirred suspension of 2,5-dioxo-6-phenylpiperidine (38 g,0.2mol) in methanol (600 mol), and stirring was continued for a further30 mins. The solvent was removed under reduced pressure, the residue wasthen azeotroped with toluene (2×150 ml). To the residue was addedBH₃.THF (317 ml of a 1M soln in THF, 0.317 mol) and the colourlesssolution heated at reflux for 16hr, then coiled to 0° C. Excess boranewas quenched by the cautious addition of methanol (50 ml), and thesolvent was then removed under reduced pressure. The residue wasdissolved in ethanol (300 ml), anhydrous K₂ CO₃ (21 g, 0.15 mol) wasadded and the mixture heated at reflux for 7 hr. After cooling to roomtemperature the solvent was removed at reduced pressure and the residuedissolved in water (200 ml) and extracted with dichloromethane (4×250ml). The combined organic extracts were then washed with brine (150 ml),dried (MgSO₄) and concetrated under reduced pressure to afford the crudehydroxy amine (21 g) as a crystalline white solid, consisting of a 11:1mixture of cis/trans isomers.

This crude material was dissolved in methanol (290 ml) and4-toluenesulphonic add (38 g, 0.3 mol) added. The precipitated solid wasrecrystallised from methanol to yield(+)-cis-3-hydroxy-2-phenylpiperidine4-toluenesulphonate salt (56.7 g,81%) as a white crystalline solid: m.p. 266°-271° C.; ¹ H NMR (360 MHz,DMSO-d₆) δ1.66 (1H, m,), 1.64 (2H, m, ), 2.02 (1H, m,) 2.29 (3H, s, Me),3.06 (1H, dr, J=3.01, 12.9 Hz, NCHH), 3.26 (1H, dd, J=12.9 Hz, NCHH),3.96 (1H, bs, CHOH), 4.35 (1H, s, OH), 5.40 (1H, d, J=3.9, NCHPh), 7.10(2H, d, J=7.9 Hz, Tosylate ArH), 7.34-7.42 (5H, m, Ph), 7.46 (2H, d,J=7.9 Hz, Tosylate ArH); Calculated for C₁₈ H₂₃ NO₄ S C, 61.87; H, 6.63;N, 4.01. Found C, 61.65; H, 6.63; N, 4.02.

d) (2S,3S)-3-Hydroxy-2-phenylyiperidinium(-)-dibenzoyl tartrate salt

(±)-cis-3-Hydroxy-2-phenylpiperidine 4-toluenesulphonate salt (Example1c, 218.5 g, 0.626 mol) was dissolved in a mixture of dichloromethane(2500 ml), methanol (250 ml) and 10% aqueous sodium carbonate solution(1400 ml). The organic phase was separated and washed with 10% aqueoussodium carbonate solution (500 ml) followed by brine (saturated, 500 ml)after drying (K₂ CO₃), the solvent was removed at reduced pressure toafford the free base (106 g).

The free base (106.4 g, 0.60 mol) was dissolved in methanol (250 ml) anda solution of (-) dibenzoyl tartaric acid (59.2 g, 0.165 mol) inmethanol (250 ml) added. The solution was cooled to 0° C. and theprecipitate isolated by filtration to yield (2S,8S)-3-hydroxy-2-phenyliperidinium (-)-dibenzoyltartrate salt (59.31 g)(ee>98%, HPLC*). The mother liquors were dissolved in 10% aqueous sodiumcarbonate solution (1000 ml) and extracted with dichloromethane (1000ml), dried (K₂ CO₃) and evaporated to afford the free residual free base(77 g). This was dissolved in methanol (200 ml) and a solution of (+)dibenzoyl tartaric acid (59.2 g, 0.165 mol) in methanol (150 ml) added.Cooling and filtration afforded (2R, 3R)-3-hydroxy-2-phenylpiperidinium(+)-dibenzoyltartrate salt (82.6 g) (ee 97.3%, HPLC*). The motherliquors were again recycled to give a second crop of (2S,3S)-3-hydroxy-2-phenylpiperidinium (-)-dibenzoyltratrate salt 34.3 g)(ee 97.6%, HPLC*). The combined crops of(2S,3S)-3-hydroxy-2-phenylpiperidinium (-)-dibenzoyltartrate salt wererecrystallised from aqueous ethanol (500 ml) to yield (2S,3S)-3-hydroxy2-phenylpiperidiumium (-)-dibenzoyltartrate salt (84.53,75.7% of available enantiomer) (ee>99.5%, HPLC*): m.p. 221°-222° C.:Calculated for C_(2O) H₂₂ NO₅ C, 67.40; H, 6.22; N, 3.93%. Found C,67.34; H, 6.23; N, 4.00%.

HPLC* ChiraI HPLC determination: ULTRON ^(R) ES-OVM Column (150 mm ×4.6mm id, 5 νm) 0.5% Ethanol in 10 mM K2HPO₄ (pH 7.5) at 1.5 ml/min, OD 210nM.

e) (2S,3S)-1-t-Butyloxycarbonyl-3-hydroxy-2-phenyl piperidine

(2S,3S)-3-Hydroxy-2-phenylpiperidinium (-)-dibenzoyl tartrate salt (71.6g, 0.20 mol) was dissolved in dichloromethane (1000 ml) at 35° C., and asolution of sodium carbonate (41 g, 0.39 mol) in water (200 ml) wasadded and the mixture was heated (stem bath) until all the solid haddissolved (a small amount of methanol was added to aid dissolution). Theorganic phase was separated and the aqueous phase extracted withdichloromethane (2×300 ml). The combined organic phases were wished withaqueous sodium carbonate (2×100 ml, saturated), dried (K₂ CO₃) andconcentrated at reduced pressure to afford (2S,3S)-3-hydroxy-2-phenylpiperidine (35 g, 100%) as a white crystallinesolid, m.p. 93°-95° C.; [α]_(D) =+98.5 (c=1, methanol).

This aminoalcohol (34 g, 0.19 mol) was dissolved in anhydrousdichloromethane (500 ml) under a nitrogen atmosphere, and di-t-butyldicarbonate (44 g, 0.20 mol) was added portionwise with stirring. Thereaction mixture was then stirred at room temperature for 18 hr, beforethe solvent was then removed at reduced pressure and the residuecrystallised from hexane to afford(2S,3S)-1-t-butyloxycarbonyl-3-hydroxy-2-phenylpiperidine (50 g, 100%)mp=66°-67° C.: ¹ H NMR (360 MHz, CDCl₃) 1,46 (9H, s, t-Bu), 1.66-1.88(4H, m, 2×CH₂), 3.1 (1H, ddd, J=2.8, 12.6, 12.6 Hz, CHHN), 3.92-4.12(2H, m, CHOH, CHHN), 5.43 (H, d, J=5.6 Hz, NCHPh), 7.34-7.47 (3H, m,AR), 7.40-7.55 (2H, m, Ar).

f) 1-(3,5bis(trifiuoromethyl)phenyl)-1-hydroxyethane

Method A

To a cooled (-20° C.) solution of 3,5-bis(trifiuoromethyl)benzaldehyde(11.0 g) in anhydrous diethyl ether (30 ml) was added a solution ofmethylmagnesium bromide (20 ml, 3M in diethyl ether). After stirring thesolution at -20° C. for 15 minutes and at ambient temperature for 30minutes, water was added dropwise. Ethyl acetate and Saturated NH₄ Clwere added and the organic phase washed with saturated brine and dried(MgSO₄). Removal of the solvent in vacuo and recrystallisation from hothexane gave1-(3,5-bis(trifiuoromethyl)phenyl)-1-hydroxyethane, 9.0 g.

Method B

To a solution of 3,5-bis(trifiuoromethyl)aeetophenone (18.4 g) inmethanol (40 ml) was slowly added sodium borehydride (2.72 g) withcooling in a water bath at 20° C. After 30 minutes ethyl acetate (200ml) and saturated NH₄ Cl (50ml) were added and the organic phase washedwith water (twice 50 ml), saturated brine and dried (MgSO₄). Evaporationand recrystallisation from hot hexane gave1-(3,5-bis(trifluoromethyl)phenyl)-1-hydroxyethane 17.4 g ¹ H NMR(250MHz, CDCl₃) δ7.84 (2H; s; 2,6-arylH), 7.79 (1H; s; 4-arylH), 5.03(2H; q, J=6.5 Hz; CH₃ CH), 1.54 (3H; d, J=6.5 Hz; CH₃).

g) 1-(3,5-bis(trifluoromethyl)phenyl)-1-bromoethane

To 1-(3,5-bis(trifiuoromethyl)phenyl)-1-hydroxyethane (10 g) was addedphosphorous tribromide (3.7 ml) to give a clear solution. After 30minutes the solution was added to water (300 ml) and the solutionstirred for a further 30 minutes. Petroleum ether bp=60°-80° C. wasadded and the organic solution washed with water (×3), saturated,NaHCO₃, saturated brine and dried (MgSO₄). The solution was evaporatedin vacuo and the residue distilled b₁₋₄ mm =69° C. to give1-(3,5-bis(trifluoromethyl)phenyl)-1-bromoethane- ¹ H NMR (250 MHz;CDCl₃) δ7.88 (2H; s; 2,6-arylH), 7.80 (1H; s; 4-arylH), 5.23 (2H,; q, J=6.9 Hz; CH₃ CH), 2.09 (3H; d, J =6.9 Hz; CH₃).

h) (2S,3S)3-(1-(3,5-bis(trifluoromethyl)phenyl)ethyloxy)-N-t-butoxycarbonyl-2-phenylpiperidine

A solution of (28,38) 1-t-butoxycarbonyl-3-hydroxy-2-phenylpiperidine(Example 1e, 0.51 g) and sodium hydride (80% suspension in oil (0.084 g)in tetrahydrofuran (5 ml) and N,N-dimethylformamide (1 ml) was sonicatedin a water bath under an atmosphere of nitrogen for 30 minutes followedby addition of 1-(3,5-bis(trifhoromethyl))-1-bromoethane (Example 1g,1.19 g). After stirring the solution for 2h a further addition of sodiumhydride (0.084 g) and 1-(3,5-bis(trifluoromethyl)-1-bromoethane wasmade. After an additional 1h, water was carefully added followed byethyl acetate and the organic phase washed with water (×3), saturatedbrine and dried (MgSO₄). After removal of the solvent in vacuo theresidual oil was chromatographed on silica gel eluting successively with0, 5%, 10% ethyl acetate in hexane to give (2S,3S)3-(1-(3,5-bis(trifluoromethyl)phenylethyloxy)-N-t-butoxycarbonyl-2-phenylpiperidine as two separatediastereomers.

i) (2S,3S)3-(1-(3,5-bis(trifluoromethyl)phenyl)ethyloxy)-2-phenylpiperidinehydrochloride salt

The individual diastereomers of the N-t-butoxycarbonyl derivative(Example 1b, 222.5mg) were treated with 2M HCl in methanol (5 ml) for2.5h. The solution was evaporated to dryness and on addition of diethylether the resultant solid was removed by filtration.

Diastereomer A mp=256°-263° C., ¹ H NMR (DMSOd₆, 360 MHz) δ8.04 (2H; s;2,6-arylH), 8.00 (1H; s; 4-arylH), 7.55-7.40 (5H; m; aryl), 4.5 (2H; m),3.96 (1H; s), 3.06 (1H; t), 1.7 (3H; m), 1.60 (1H; bd), 0.89 (3H; d,J=6.4 Hz, CH₃).

Diastereomer B (after chromatography in chloroform: acetic acid:methanol 85:5:10, evaporation and hydrochloride salt formation)mp=302°-312° C.; m/z CI+=418(M+H), CI-=416(M-H). ¹ H NMR (DMSOd₆, 360MHz) δ7.86 (1H; s; 4-aryl1H), 7.49 (2H; s; 2,6-arylH), 7.36-7.30 (1H; m;aryl), 4.76 (1H; q; J=6.28 Hz; CH₃ CH), 4.42 (1H; s), 3.60 (1H; s), 3.06(1H; t), 2.28 (1H; d), 2.01 (1H; m), 1.72 (2H; m), 1.38 (3H; d, J=6.4Hz; CH₃).

EXAMPLE 2 5-[(2S,3SR)3-[1-(3,5-Bis(trifluoromethyl)phenyl)ethoxyl]2-phenylpiperidin-1-ylmethyl]-2.4-dihydro-[1,2,4]triazol-3-one

a) To a cooled (0° C.) solution of chloroacetonitrile (54.1 g) inmethanol (100 ml) was added dropwise a solution of 1M-sodium mothoxide(20 ml). After stirring the solution at 0° C. for 30 mins glacial aceticacid (1.2 ml) was added followed by a solution of methyl carbazate (64.5g, fleshly distilled in vacuo) in warmed dimethyl formamide (35 ml) andmethanol (300 ml). After stirring the solution at 0° C. for 30 minutesthe crystalline solid which had formed was removed by filtration andwashed with ethyl acetate to give N-carbomethoxy-2-chloroacetamidrazone,mp=138°-140° C.

b) To a solution of diastereomer B (Example 1i, 2.0 g)indimethylformamide (10 ml) was added K₂ CO.sub. 3 (3.04 g) andN-carbomethoxy-2-chloroacetamidrazone (Example 2a, 0.876 g). Thesolution heated at 80° C. for 1h then partitioned between ethyl acetateand water. The organic phase was washed with water and saturated brineand dried (MgSO₄). Upon removal of the solvent in vacuo the residualfoam was dissolved in xylene (40 ml) and the solution heated to 140° C.for 6h. The solution was evaporated and the residue purified by col-ranchromatography on silica gel eluting with 0% and 4% methanol indichloromethane to give the title compound. mp=214°-215° C. m/z(CI+)=515 (M+H).

EXAMPLE 35-[(2S,3S,R)-3-[1-(3,5-Bis(trifiuoromethyl)phenyl)ethoxy]-2-phenylpiperidin-1-ylmethyl]-[1.2.4]triazole

a) To a cooled (0° C.) solution of chloroacetonitrile (10 g) in methanol(8 ml) was added 1M-sodium methoxide (3.4 ml). After 30 minutes at 0° C.glacial acetic acid (0.22 ml) was added followed by dropwise addition ofa solution offorrnle acid hydrazide (7.9 g) in warmed methanol (30 ml).After the solution had been stirred at 0° C. for 15 minutes ethylacetate (30 ml) were added. After 30 minutes at 0° C. the crystallinesolid which had formed was removed by filtration and washed with ethylacetate and diethyl ether to give N-formyl-2-chloroacetamidohydrazonemp=119°-120° C.

b) To a solution ofdiastereomer B (Example 1i, 0.4 g) indimethylforrnamide (2 ml) was added K₂ CO₃ (0.68 g) andN-formyl-2-chloroacetamidohydrazone (Example 2a). The solution wasstirred at room temperature for 2h then at 100° C. for 2h. The solutionwas cooled and the residue purified by chromatography on silica gel(eluting with 4% methanol/dichloromethane) to give the title compoundmp=182°-183° C.

EXAMPLE 45-[1-[(2S,3S,R)-3-[1-(3,5-bis(trifluoromethyl)phenyl)ethoxy]-2-phenylpiperidin-1-yl]ethyl]-2,4-dihydro-[1,2,4]triazol-3-one

a) To a cooled (0° C.) solution of α-chloropropionitrile (5.9 g) wasadded 0.3M-sodium methoxide (6 ml). After stirring the solution for0.75h glacial acetic acid (0.11ml) was added followed by a solution ofmethyl carbazate (5.2 g, freshly distilled in vacuo) in warmed dimethylformamide (8 ml). After stirring the solution at 0° C. for 0.5h thesolution was evaporated to a small volume and diethyl ether (50 ml)added. The crystalline solid was removed by filtration and washed withdiethyl ether to give N-carbomethoxy-2-chloropropionamidrazone.

b) To a solution of diastereomer B (Example 1i, 0.096 g) indimethylformamide (2 ml) was added K₂ CO₃ (0.146 g) andN-carbomethoxy-2-chloropropionamidrazone (0.046 g, Example 4a). Thesolution was stirred at 100° C. for 2h and 140° C. for 2h. The cooledsolution was chromatographed on silica gel (eluting with 4%methanol/dichloromethane). The product was crystallized from diethylether to give the title compound mp=257°-258° C.

EXAMPLE 5 (2S,3S)-3-(1(3,5-Dichlorophenyl)ethyloxy)-2-phenylpiperidinehydrochloride.

The title compound was prepared by a method analogous to that describedin Example 1. mp>250° C.

EXAMPLE 65-[(2S,3S,R)-3-[1-(3,5-Dichlorophenyl)ethyloxy]-2-phenylpiperidin-1-ylmethyl]-2,4-dihydro][1,2,4]-triazol-3-one.

The title compound was prepared from the product of Example 5 by aprocedure analogous to that described in Example 2. m/z (CI+)=447, 449.Mp 191°-192° C.

EXAMPLE 7 (2S,3S)-3-(1-(Phenyl)ethyloxy)-2-phenylnpiperidinehydrochloride

The title compound was prepared by an analogous procedure to thatdescribed in Example 1, mp=259°-268° C.

EXAMPLE 85-[(2S,3S,R)-3-[1-(Phenyl)ethyloxy]-2-phenylpiperidin-1-ylmethyl]-2,4-dihydro-[1,2,4]-triazol-3-one

The title compound was prepared from the product of Example 7 by aprocedure analogous to that described in Example 2. Mp =211°-213° C.

EXAMPLE 9 (2S,3S)-3-(1-(3-Chlorophenyl)ethyloxy)-2-phenylpiperidinehydrochloride

The title compound was prepared by a method analogous to that describedin Example 1. Mp =273°-276° C.

EXAMPLE 105-[(2S,3S,R)-3-[1-(3-Chlorophenyl)ethyloxy)-2-phenylpiperidin-1-ylmethyl]-2,4-dihydro-[1,2,4]triazol-3-one

The title compound was prepared from the product of Example 9 by aprocedure analogous to that described in Example 2. Mp=164°-165° C.

EXAMPLE 11 2S,3S)-3-(1-(3-isopropoxyphenyl)ethyloxy]-2-phenylpiperidinehydrochloride

The title compound was prepared by a method analogous to that describedin Example 1, Mp=253°-256° C.

EXAMPLE 125-[(2S,3S,R)-3-[1-[3-Isopropoxphenyl)ethyloxy]-2-phenylpiperidin-1-1methyl]-2,4-dihydro-[1,2,4]triazol-3-one

The title compound was prepared from the product of Example 11 by aprocedure analogous to that described in Example 2. Mp=104°-106° C.

EXAMPLE 13(2S,3S)-3-(1-(3,5-Bis(trifiuoromethyl)ohenyl)ethyloxy)-2-(4-fluorophenyl)piperidinehydrochloride

The title compound was prepared by a procedure analogous to thatdescribed in Example 1 using 4-fluorobenzaldehyde to give diastereomerB: mp=265°-266° C.

EXAMPLE 14 5-[(2S,3S,R)-3-[1-(3,5-Bis(trifiuoromethyl)phenyl)ethoxy]-2-[4-fluorophenyl)pineridin-1-ylmethyl]-2,4-dihydro-[1,2,4]triazo]-3-one

The title compound was prepared from the product of Example 13 by aprocedure analogous to Example 2. Mp=222°-223° C.

EXAMPLE 15 5-[2S,3S,R)-3-[1-(3,5-Bis(trifluoromethyl)phenyl)ethoxy]-2-(4-fluorophenyl)piperidin-1-ylmethyl]-[1,2,4]triazole

The title compound was prepared from the product of Example 13 by aprocedure analogous to Example 3. mp=175°-177° C.

EXAMPLE 165-[(2S,3S,R),3-(3-Chloro-5-t-butyl)phenyl)ethyloxyl-2-(4-fluorophenyl)piperidin-1-ylmethyl]-2,4-dihydro-[1,2,4]triazol-3-one

The title compound was prepared from(2S,3S)-1-t-butyloxycarbonyl-3-hydroxy-2-(4-fluorophenyl)piperidine(prepared as intermediate in Example 13) using procedures analogous tothose described in Examples 1h, 1i, 2. Mp=213° C.

EXAMPLE 17 (2S,3S,R)-3-(1-(3-Trifluoromethylphenyl)ethyloxy)-2-phenylpiperidinehydrochloride

The title compound was prepared by a method analogous to that describedin Example 1, m/z (CI+)=850 (M+H).

EXAMPLE 18

5-[(2S,3S,R)-3-[1-(3-Trifluoromethylphenyl)ethyloxy]2-phenylpiperidin-1-ylmethyl]-2,4-dihydro-[1,2,4]triazol-3-one

The title compound was prepared from fie product of Example 17 by aprocedure analogous to that described in Example 2. Mp=143°-145°C.

EXAMPLE 19 [2S,3S,R)-3-(1-[3-Bromophenyl)ethyloxy)-2-phenylpiperidinehydrochloride

The title compound was prepared by a method analogous to that describedin Example 1. Mp=267°-268° C.

EXAMPLE 205-[(2S,3S,R)-3-[1-(3-Bromophenyl)ethyloxy]-2-phenylpiperidin-1-ylmethyl]-2,4-dihydro-[1,2,4]triazol-3-one

The title compound was prepared from the product of Example 19 by aprocedure analogous to that described in Example 2. Mp=165° C.

EXAMPLE 21(2S,3S,R)-3-[1-(2-Chloro-5-trifluoromethylphenyl)ethyloxyl]-2-(4-fluorophenyl)piperidinehydrochloride

The title compound was prepared from(2S,3S)-1-t-butyloxycarbonyl-3-hydroxy-2-(4-fluorophenyl)piperidine(prepared as intermediate in Example 13) using procedures analogous tothose described in Examples 1h, 1i. Mp=272°-273° C.

EXAMPLE 22 5-[2S,3S,R)-3-[-(2-Chloro-5-trifluoromethylyphenyl)ethyl[oxy]-2-(4-fluoroyhenyl)piperidin-1-ylmethyl]-2,4-dihydro-[1.2.4]triazol-3-one

The title compound was prepared from the product of Example 21 by aprocedure analogous to that described in Example 2. Mp=208°-209° C.

We claim:
 1. A compound of formula (I), or a salt thereof: ##STR14##wherein n is 3 and where any carbon atom of (CH₂)_(n) may be substitutedby R⁴ and/or R⁵ ;X represents O or S; R¹ represents (CH₂)_(q) phenyl,wherein q is 0, 1, 2 or 3, which may be optionally substituted in thephenyl ring by 1, 2 or 3 groups selected from C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, halo, cyano, nitro, trifluoromethyl, trimethylsilyl,--OR^(a), SR^(a), SOR^(a), SO₂ R^(a), --NR^(a) R^(b), --NR^(a) COR^(b),--NR^(a) CO₂ R^(b), --CO₂ R^(a) and --CONR^(a) R^(b) ; R² representsaryl selected from phenyl and naphthyl; heteroaryl selected fromindazolyl, thienyl, furyl, pyridyl, thiazolyl, tetrazolyl and quinolyl;moiety may be substituted by C₁₋₆ alkyl, C₁₋₆ alkoxy halo benzhydryl; orbenzyl; wherein each aryl or heteroaryl or trifluoromethyl; R⁴ and R⁵each independently represent H, halo, C₁₋₆ alkyl, CO₂ ^(R) ^(a) orCONR^(a) R^(b) or R⁴ and R⁵ together form an oxo; R⁶ represents H orC₁₋₆ alkyl; R⁷ represents C₁₋₆ alkyl or phenyl optionally substituted by1, 2 or 3 groups selected from C₁₋₆ alkyl.sub., C₂₋₆ alkenyl, C₂₋₆alkynyl, halo, cyano, nitro, trifluoromethyl, trimethylsilyl, --OR^(a),SR^(a), SOR^(a), SO₂ R^(a), NR^(a) R^(b), --NR^(a) COR^(b), --NR^(a) CO₂R^(b), --CO₂ R^(a) and --CONR^(a) R^(b) ; R⁸ represents H, COR^(a), CO₂R^(a), COCONR^(a) R^(b), COCO₂ R^(a), C₁₋₆ alkyl optionally substitutedby a group selected from (CO₂ R^(a), CONR^(a) R^(b), hydroxy, cyano,COR^(a), NR^(a) R^(b), C(NOH)NR^(a) R^(b), CONHphenyl(C₁₋₄ alkyl), COCO₂^(R) ^(a), CONRHNR^(a) R^(b), C(S)NR^(a) R^(b), CONR^(a) C₁₋₆ alkylR¹²,CONR¹³ C₂₋₆ alkynyl, CONR¹³ C₂₋₆ alkenyl, COCONR^(a) R^(b), CONR^(a)C(NR^(b))NR^(a) R^(b), CONR^(a) heteroaryl, wherein heteroaryl isdefined above, and phenyl optionally substituted by one or moresubstituents selected from C₁₋₆ alkyl, C₁₋₆ alkoxy, halo andtrifluoromethyl) or C₁₋₆ alkyl, optionally substituted by oxo,substituted by an aromatic heterocyclic group selected from thienyl,furyl, pyrrolyl, pyridyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl,pyrazinyl, pyridazinyl, oxazolyl, oxadiazolyl, thiadiazolyl, isoxazolyl,quinolyl, isothiazolyl, imidazolyl, benzimidazolyl, benzoxazolyl,benzothiophenyl, benzofuranyl and indolyl, which group is optionallysubstituted by C₁₋₆ alkyl, C₁₋₆ alkxy, oxo, thioxo, halo,trifluoromethyl, N^(R) ^(a) R^(b), NR^(a) COR^(b), CONR^(a) R^(b), CO₂R^(a), SO₂ R^(a) and CH₂ OR^(a), where R^(a) and R^(b) are as previouslydefined; R^(a) and R^(b) each independently represent H, C₁₋₆ alkyl,trifluoromethyl or phenyl optionally substituted by C₁₋₆ alkyl, halo ortrifluoromethyl; R¹² represents OR^(a), CONR^(a) R^(b) or heteroaryl;and R¹³ represents H or C₁₋₆ alkyl.
 2. A compound as claimed in claim 1of formula (Ia), or a salt thereof: ##STR15## wherein R², R⁴, R⁵, R⁶,R⁸, X and n are as defined for formula (I) above;R¹⁵ represents C₁₋₆alkyl; and R¹⁶ represents phenyl optionally substituted by 1, 2 or 3groups selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, halo,cyano, nitro, trifluoromethyl, trimethylsilyl, --OR^(a), SR^(a),SOR^(a), SO² R^(a), --NR^(a) R^(b), --NR^(a) COR^(b), --NR^(a) CO₂R^(b), --CO₂ R^(a) and --CONR^(a) R^(b).
 3. A compound as claimed inclaim 1 of formula (Ib) or a salt thereof: ##STR16## wherein Xrepresents O or S;R⁸ is as defined for formula (I); R¹⁷ representsphenyl or benzhydryl wherein any of the phenyl rings of the phenyl orbenzhydryl moieties may optionally be substituted by halo ortrifluoromethyl, preferably unsubstituted phenyl; R¹⁸ is methyl; R¹⁹ isH or methyl; and R²⁰ and R²¹ independently represent H C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, chloro, bromo, fluoro, iodo, cyano, nitro,trifluoromethyl, trimethylsilyl OR^(a), SR^(a), SOR^(a), SO₂ R^(a),NR^(a) R^(b), NR^(a) COR^(b), NR^(a) CO₂ R^(b), CO₂ R^(a), or CONR^(a)R^(b), where R^(a) and R^(b) are as previously defined.
 4. A compound asclaimed in claim 1 wherein n is
 3. 5. A compound as claimed in claim 1claim wherein X is O.
 6. A compound as claimed in claim 1 claim whereinq is O and R¹ represents phenyl substituted by one or more groupsselected from methyl, trifluoromethyl, chloro and t-butyl.
 7. A compoundas claimed in claim 1 wherein R² represents unsubstituted benzhydryl,phenyl substituted by halo or unsubstituted phenyl.
 8. A compound asclaimed in claim 1 wherein R⁶ represents H or methyl.
 9. A compound asclaimed in claim 1 wherein R⁷ is methyl or ethyl.
 10. A compound asclaimed in claim 1 wherein R⁸ represents CH₂ -Het, CH(CH₃)-Het, C(CH₃)₂-Het or C(O)-Het where Het is substituted or unsubstituted oxazolyl,oxadiazolyl, tetrazolyl, thiazolyl, thiadiazolyl, furanyl, thienyl,triazolyl, pyrazinyl, pyridyl, pyridazinyl, imidazolyl orbenzimidazolyl.
 11. A compound selected from(2S,3S)3-(1-(3,5-bis(trifluoromethyl)phenyl)ethyloxy)-2-phenylpiperidine;or a salt or prodrug thereof.
 12. A pharmaceutical compositioncomprising a compound as claimed in claim 1 in association with apharmaceutically acceptable carrier.
 13. A process for the preparationof a compound as claimed in claim i which process comprises reacting acompound of formula (II) with a compound of formula (III) ##STR17##wherein one of R³⁰ and R³¹ represents a leaving group selected from:chloro, bromo, iodo, tosylate, mesylate, and triflate; and the other ofR³⁰ and R³¹ represents XH, wherein X is as defined in claim 1; and, ifnecessary or desired, converting the compound of formula (I) so preparedinto another compound of formula (I), or a salt or prodrug thereof. 14.A method for the treatment or prevention of physiological disordersassociated with an excess of tachykinins, which method comprisesadministration to a patient in need thereof of a tachykinin reducingamount of a compound according to claim 1, or a salt thereof, or acomposition comprising a compound according to claim 1, or a saltthereof.
 15. A method according to claim 14 for the treatment orprevention of pain or inflammation.
 16. A method according to claim 14for the treatment or prevention of migraine.
 17. A method according toclaim 14 for the treatment or prevention of emesis.